CN103405766A - Bevacizumab eye drop and preparation method thereof - Google Patents
Bevacizumab eye drop and preparation method thereof Download PDFInfo
- Publication number
- CN103405766A CN103405766A CN2013103374261A CN201310337426A CN103405766A CN 103405766 A CN103405766 A CN 103405766A CN 2013103374261 A CN2013103374261 A CN 2013103374261A CN 201310337426 A CN201310337426 A CN 201310337426A CN 103405766 A CN103405766 A CN 103405766A
- Authority
- CN
- China
- Prior art keywords
- bevacizumab
- eye drop
- osmotic pressure
- regulator
- injection
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
The invention relates to a bevacizumab eye drop and a preparation method thereof. The bevacizumab eye drop comprises the following components: 0.25-25 g/L of bevacizumab, 0.1-25 g/L of thickening agent, 0.1-25 g/L glycerol, 0.025-1.0 g/L of protein protecting agent and 2.5-12.5 g/L of osmotic pressure regulator, and the PH of the eye drop is adjusted to 5.0-7.5. The eye drop provided by the invention can prevent medicine from overflow and loss, enables medicine to remain in the focal zone for a long time, can perform the function of lubricating the cornea, and increases the bioavailability of bevacizumab. In addition, glycerol is added to prolong the storage time of the bevacizumab eye drop.
Description
Technical field
The present invention relates to field of biological product, particularly relate to a kind of bevacizumab eye drop and preparation method thereof.
Background technology
Cornea rebirth blood vessel (corneal neovascularization, CNV) is multiple eye surface diseases such as serious chemistry and the common pathological characters of thermal burn, infection, degeneration or wound etc.Can reduce Corneal transparency, cause " immune privilege " function of significant visual deterioration, corneal scarring, lipidosis, change cornea, and make the rejection after corneal transplantation increase, cause the failure of penetrating keratoplasty.The method for the treatment of is a lot of at present, but effect is unsatisfactory.The research in recent years demonstration, VEGF (vascular endothelial growth factor, VEGF) plays an important role in corneal neovascularization.In the cornea of zoopery discovery inflammation and vascularization, VEGF obviously raises.The experiment confirm of Lai etc. specific downward VEGF generate, can significantly reduce the formation of cornea rebirth blood vessel.Therefore, inquire into the application of VEGF antagonist in the cornea rebirth blood vessel disease and have important clinical meaning and practical value for prevention and treatment eye table neovascular diseases.
Bevacizumab (Bevacizumab), trade name Arastin (Avastin), be the restructuring Mus monoclonal IgG1 antibody of novel human-derivedization anti-vascular endothelial growth factor, molecular weight is 149kDa.Bevacizumab can be combined with 5 kinds of hypotypes of VEGF-A, the main mechanism of its anti-new vessels is for stoping the VEFG receptors bind of VEFG and endothelial cell surface, the biological activity of endogenousization VEGF was lost efficacy, suppress endothelial cell mitogen, reduce vascular permeability, thereby hinder the formation of new vessels.First got permission listing in the U.S. as the medicine that suppresses tumor angiogenesis from bevacizumab in 2004, and bevacizumab is introduced into field of ophthalmology subsequently, is widely used in the control of optical fundus neovascular diseases.It mainly treats the fundus oculi diseases such as macular edema that choroidal neovascularization, wet age related macular degeneration, diabetes, branch retinal vein occlusion remaining etc. cause and retinal neovascularization by intravitreal, and has obtained sure curative effect.Yet bevacizumab is relatively less in the research of eye table new vessels, still under test, shortage can be directly used in local application's preparation of the treatment eye surface diseases of clinical use.At present for bevacizumab, the eye topical mode of the experimentation of eye table rebirth blood vessel function is had to two kinds, a kind of mode commonly used is direct drug injection thing eye drip, another kind of for after entering drug injection under bulbar conjunctiva, by the sclera invasion, enter corneal stroma and the corneoscleral junction tissue enters ophthalmic.While using drug administration by injection, local irritation is large, and the pain that the patient often has does not to a certain degree accommodate the danger that punctures eyeball.Mostly need repetitively administered, multiple injection easily causes subconjunctival hemorrhage and scarring, more increases the use inconvenience of this medicine.In addition, eye drop is easy to use, after eye drip, there is no the untoward reaction of whole body other system, but uses an eye table part to splash into the easy excessive loss of medicinal liquid after conjunctival sac, and dilutes with tear, and bioavailability is lower.At present, the bevacizumab solution that the zooscopy of eye table neovascular disease is used, for directly by the bevacizumab stock solution of normal saline dilution, making, the physical characteristic of this solution, there is some difference as the normal tear fluid under osmotic pressure, pH value etc. and physiological conditions, limited its use clinically.While having research observation bevacizumab inhibition alkali burn to cause Mus cornea rebirth blood vessel model, the bevacizumab topical application can effectively suppress the mouse cornea new vessels although find, but having observed simultaneously the obvious corneal opacity forms, the eye drop osmotic pressure that its supposition may be made with normal saline dilution bevacizumab stock solution is relatively low, the corneal edema caused.Therefore, find a kind of can give full play to the anti-rebirth blood vessel function of bevacizumab again to greatest extent the administering mode of complication seem particularly important.
In addition, bevacizumab belongs to monoclonal antibody, under general state, is difficult for preserving, and as easy as rolling off a log deterioration failure, even cause allergic reaction.Find a kind of protective agent of protecting bevacizumab protein, the effective time that extends bevacizumab is very important.
Hyaluronic acid sodium is the sodium-salt form of Hyaluronic Acid, is a kind of mucopolysaccharide transparent compound, and its molecular mass is 1,500,000-3,000,000 dalton.Random coil state and the hydrodynamics characteristics of hyaluronic acid sodium in solution are given it and are had many important physical characteristics, as: height viscoelasticity, plasticity, permeability, unique rheological properties and good biocompatibility, these characteristics make hyaluronic acid sodium become clinically purposes biomedical material very widely.
In a word, in eye table neovascular diseases, find a kind of bevacizumab compound medication formulation application that increases again curative effect simple to operation very necessary above clinical.The present invention breaks through every technical barrier, first bevacizumab is made into to eye drop, will show on eye the treatment generation impact greatly of neovascular disease.
Summary of the invention
According to the deficiencies in the prior art, in order to realize the topical therapeutic of bevacizumab for eye table new vessels, and the bioavailability of increase bevacizumab eye drop in the cornea rebirth blood vessel disease, increase stability and the preservation of eye drop, the invention provides bevacizumab eye drop of the little and good stability of a kind of zest and preparation method thereof.
Technical scheme provided by the invention is: the ratio that a kind of bevacizumab eye drop, described eye drop include following component and each component is:
Bevacizumab 0.25 ~ 25g/L;
Thickening agent 0.1 ~ 25 g/L;
Glycerol 0.1 ~ 25 g/L;
Protein protective agent 0.025 ~ 1.0g/L;
Osmotic pressure regulator 2.5 ~ 12.5 g/L;
And regulate the PH to 5.0 of described eye drop ~ 7.5.
The ratio that described eye drop includes following component and each component is preferably:
Bevacizumab 2.5 ~ 12.5g/L;
Thickening agent 5 ~ 12.5 g/L;
Glycerol 5 ~ 12.5 g/L;
Protein protective agent 0.125 ~ 0.5g/L;
Osmotic pressure regulator 5 ~ 10 g/L;
And regulate the PH to 5.0 of described eye drop ~ 7.5.
Described protein protective agent is human albumin, mannitol or Polyethylene Glycol.
Described osmotic pressure regulator is sodium chloride or sorbitol.
The osmotic pressure of described eye drop is 295 ~ 305mmol/L.
Described eye drop adopts the PH regulator to regulate pH value, described PH regulator be phosphoric acid buffer to, borate buffer to or hydrochloric acid/sodium hydroxide buffering right.
A kind of preparation method of bevacizumab eye drop comprises following steps:
(1) each component of weighing at first in proportion;
(2) then thickening agent is scattered in sterile water for injection, after high pressure steam sterilization, is cooled to 30 ℃-40 ℃;
(3) bevacizumab, protein protective agent, osmotic pressure regulator and PH regulator are dissolved in sterile water for injection to filtration sterilization;
(4) under gnotobasis, will after the solution mix homogeneously of the solution of step (1) gained and step (2) gained, obtain product.
Described eye drop 0.4ml packing is stored in 4 ℃.
The present invention compared with prior art, has following beneficial effect:
Hyaluronic acid sodium has rheological properties, good biocompatibility, significant hydrophilic ability and the lubrication of height viscoelasticity, plasticity, permeability, uniqueness, research is simultaneously also found, on the eye cornea endotheliocyte, contain endogenous hyaluronic acid sodium and receptor thereof, and hyaluronic acid sodium can also be combined with fibronectin, by the latter's effect, promote connection and the stretching, extension of corneal epithelial cell, thereby promote the repair in trauma of corneal epithelial cell.Have to study in the Rabbit Corneal Epithelium damage model of being in and observe iodine steam and the caused exfoliation of corneal epithelium of n-enanthol, 0.1% hyaluronic acid sodium can make wound surface significantly dwindle, and promotes corneal epithelial cell to extend.The above-mentioned characteristic of hyaluronic acid sodium can be good at bringing into play the anti-rebirth blood vessel function of bevacizumab, and helps the reparation of corneal injury.
Add certain buffer salt ion and osmotic pressure regulator, can form the physiological property near normal biological tear: as ion concentration and the acid-base value of physiological concentration, the eye drop histocompatibility is good, and comfortable vacuum response more is conducive to the reparation of eye table damage.
In addition, the protein protectant such as glycerol can increase the holding time of bevacizumab.Add these protective agents can extend holding time of bevacizumab, keep the pharmacological action of bevacizumab.
The invention provides a kind of bevacizumab eye drop of the eye of the inhibition for clinical use table new vessels, increased a kind of new method for treating clinically the cornea rebirth blood vessel disease, increased simultaneously the scope of bevacizumab treatment disease.
The present invention adds the thickening agents such as hyaluronic acid sodium, increases eye drop and shows the time of staying at eye, strengthens its bioavailability, and especially hyaluronic acid sodium has reduced the stimulation of eye drop to injured eye, increases the eye drop comfort level.
Eye drop of the present invention is the 0.4ml unit dose package, avoids adding the stimulation of antiseptic to injured eye.And unit dose package is avoided in repetition eye drip process the pollution to eye drop.
Specific implementation method
Below in conjunction with embodiments of the invention, be described further, these embodiment are interpreted as can not limiting practical range of the present invention, and its modification and equivalent way all covered in protection scope of the present invention.
Embodiment 1
Bevacizumab eye drop component:
Bevacizumab 25mg;
Hyaluronate sodium 10mg;
Glycerol 10mg;
Human albumin 2.5mg;
Sodium chloride 250mg;
Sodium dihydrogen phosphate 50mg;
Sodium hydrogen phosphate 125mg;
Water for injection adds to 100ml
Make altogether 250
The pH value recorded is 6.8.
The preparation method step of above-mentioned bevacizumab eye drop is as follows:
(1) the recipe quantity hyaluronic acid sodium is scattered in appropriate sterile water for injection to fully swelling, at 121 ° of C pressure sterilizings, be cooled to 40 ℃ standby;
(2) recipe quantity bevacizumab, human albumin, sodium chloride and sodium dihydrogen phosphate and sodium hydrogen phosphate are dissolved in appropriate sterile water for injection, with 0.22 μ m filter membrane aseptic filtration;
(3) under aseptic adjusting, the solution of the solution of step (1) gained and step (2) gained is evenly mixed, with packing immediately after the sterile water for injection standardize solution, and preserve under 4 ℃.
The present embodiment gained eye drop is carried out to the Alkali-burned Rabbit Corneas model experiment, and after discovery can make alkali burn, the new vessels time of origin postponed 1 day; Make the cornea rebirth blood vessel area in a rear week of damage reduce 20% than matched group; Make vegf protein in the rear all cornea tissues of damage express than matched group minimizing 20%; Make VEGFmRNA in the rear all cornea tissues of damage express minimizing 15%, make the interior vegf protein of the aqueous humor in a week after damaging express minimizing 25%.
Embodiment 2
Bevacizumab eye drop component:
Bevacizumab 250mg;
Hyaluronate sodium 500mg;
Glycerol 500mg;
Human albumin 12.5mg;
Sodium chloride 500mg;
Sodium dihydrogen phosphate 45mg;
Sodium hydrogen phosphate 100mg;
Water for injection adds to 100ml
Make altogether 250
The pH value recorded is 7.0.
The preparation method step of above-mentioned bevacizumab eye drop is as follows:
(1) the recipe quantity hyaluronic acid sodium is scattered in appropriate sterile water for injection to fully swelling, at 121 ° of C pressure sterilizings, be cooled to 35 ℃ standby;
(2) recipe quantity bevacizumab, human albumin, sodium chloride and sodium dihydrogen phosphate and sodium hydrogen phosphate are dissolved in appropriate sterile water for injection, with 0.22 μ m filter membrane aseptic filtration;
(3) under aseptic adjusting, the solution of the solution of step (1) gained and step (2) gained is evenly mixed, with packing immediately after the sterile water for injection standardize solution, and preserve under 4 ℃.
The present embodiment gained eye drop is carried out to the Alkali-burned Rabbit Corneas model experiment, and after discovery can make alkali burn, the new vessels time of origin postponed 1.5 days; Make the cornea rebirth blood vessel area in a rear week of damage reduce 25% than matched group; Make vegf protein in the rear all cornea tissues of damage express than matched group minimizing 30%; Make VEGFmRNA in the rear all cornea tissues of damage express minimizing 25%, make the interior vegf protein of the aqueous humor in a week after damaging express minimizing 30%.
Embodiment 3
Bevacizumab eye drop component:
Bevacizumab 2.5g;
Polyvinyl alcohol 2.5g;
Glycerol 2.5g;
Human albumin 0.1g;
Sorbitol 1.25g;
Sodium dihydrogen phosphate 0.1g
Sodium hydrogen phosphate 0.25g
Water for injection adds to 100ml
Make altogether 250
The pH value recorded is 7.0.
The preparation method step of above-mentioned bevacizumab eye drop is as follows:
(1) the recipe quantity polyvinyl alcohol is scattered in appropriate sterile water for injection, at 121 ° of C pressure sterilizings, be cooled to 30 ℃ standby;
(2) recipe quantity bevacizumab, human albumin, sorbitol and sodium dihydrogen phosphate and sodium hydrogen phosphate are dissolved in appropriate sterile water for injection, with 0.22 μ m filter membrane aseptic filtration;
(3) under aseptic adjusting, the solution of the solution of step (1) gained and step (2) gained is evenly mixed, with packing immediately after the sterile water for injection standardize solution, and under 4 °, preserving.
The present embodiment gained eye drop is carried out to the Alkali-burned Rabbit Corneas model experiment, and after discovery can make alkali burn, the new vessels time of origin postponed 2 days; Make the cornea rebirth blood vessel area in a rear week of damage reduce 35% than matched group; Make vegf protein in the rear all cornea tissues of damage express than matched group minimizing 40%; Make VEGFmRNA in the rear all cornea tissues of damage express minimizing 35%, make the interior vegf protein of the aqueous humor in a week after damaging express minimizing 40%.
Embodiment 4
Bevacizumab eye drop component:
Bevacizumab 1.25g;
Hyaluronate sodium 1.25g;
Glycerol 1.25g;
Human albumin 0.05g;
Sodium chloride 1g;
Sodium dihydrogen phosphate 0.045g;
Sodium hydrogen phosphate 0.1g;
Water for injection adds to 100ml
Make altogether 250
The pH value recorded is 7.0.
The preparation method step of above-mentioned bevacizumab eye drop is as follows:
(1) the recipe quantity polyvinyl alcohol is scattered in appropriate sterile water for injection, at 121 ° of C pressure sterilizings, be cooled to 30 ℃ standby;
(2) recipe quantity bevacizumab, human albumin, sorbitol and sodium dihydrogen phosphate and sodium hydrogen phosphate are dissolved in appropriate sterile water for injection, with 0.22 μ m filter membrane aseptic filtration;
(3) under aseptic adjusting, the solution of the solution of step (1) gained and step (2) gained is evenly mixed, with packing immediately after the sterile water for injection standardize solution, and preserve under 4 ℃.
The present embodiment gained eye drop is carried out to the Alkali-burned Rabbit Corneas model experiment, and after discovery can make alkali burn, the new vessels time of origin postponed 2.5 days; Make the cornea rebirth blood vessel area in a rear week of damage reduce 50% than matched group; Make vegf protein in the rear all cornea tissues of damage express than matched group minimizing 45%; Make VEGFmRNA in the rear all cornea tissues of damage express minimizing 40%, make the interior vegf protein of the aqueous humor in a week after damaging express minimizing 50%.
Claims (8)
1. bevacizumab eye drop, it is characterized in that: the ratio that described eye drop includes following component and each component is:
Bevacizumab 0.25 ~ 25g/L;
Thickening agent 0.1 ~ 25 g/L;
Glycerol 0.1 ~ 25 g/L;
Protein protective agent 0.025 ~ 1.0g/L;
Osmotic pressure regulator 2.5 ~ 12.5 g/L;
And regulate the PH to 5.0 of described eye drop ~ 7.5.
2. bevacizumab eye drop as claimed in claim 1, it is characterized in that: the ratio that described eye drop includes following component and each component is:
Bevacizumab 2.5 ~ 12.5g/L;
Thickening agent 5 ~ 12.5 g/L;
Glycerol 5 ~ 12.5 g/L;
Protein protective agent 0.125 ~ 0.5g/L;
Osmotic pressure regulator 5 ~ 10 g/L;
And regulate the PH to 5.0 of described eye drop ~ 7.5.
3. bevacizumab eye drop as claimed in claim 1 or 2, it is characterized in that: described protein protective agent is human albumin, mannitol or Polyethylene Glycol.
4. bevacizumab eye drop as claimed in claim 1 or 2, it is characterized in that: described osmotic pressure regulator is sodium chloride or sorbitol.
5. bevacizumab eye drop as claimed in claim 1 or 2, it is characterized in that: the osmotic pressure of described eye drop is 295 ~ 305mmol/L.
6. bevacizumab eye drop as claimed in claim 1 or 2 is characterized in that: described eye drop adopts the PH regulator to regulate pH value, described PH regulator be phosphoric acid buffer to, borate buffer to or hydrochloric acid/sodium hydroxide buffering right.
7. the preparation method of the described bevacizumab eye drop of claim 1 or 2 is characterized in that: comprise following steps:
(1) each component of weighing at first in proportion;
(2) then thickening agent is scattered in sterile water for injection, after high pressure steam sterilization, is cooled to 30 ℃-40 ℃;
(3) bevacizumab, protein protective agent, osmotic pressure regulator and PH regulator are dissolved in sterile water for injection to filtration sterilization;
(4) under gnotobasis, will after the solution mix homogeneously of the solution of step (1) gained and step (2) gained, obtain product.
8. bevacizumab eye drop as claimed in claim 7, it is characterized in that: described eye drop 0.4ml packing is stored in 4 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310337426.1A CN103405766B (en) | 2013-08-06 | 2013-08-06 | A kind of bevacizumab eye drop and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310337426.1A CN103405766B (en) | 2013-08-06 | 2013-08-06 | A kind of bevacizumab eye drop and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103405766A true CN103405766A (en) | 2013-11-27 |
| CN103405766B CN103405766B (en) | 2016-01-06 |
Family
ID=49598837
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310337426.1A Active CN103405766B (en) | 2013-08-06 | 2013-08-06 | A kind of bevacizumab eye drop and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103405766B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102548548A (en) * | 2009-06-10 | 2012-07-04 | 米拓科技有限责任公司 | Pharmaceutical composition for use in medical and veterinary ophthalmology |
| CN102988301A (en) * | 2012-12-26 | 2013-03-27 | 温州医学院 | Preparation method of long-acting sustained-release microspheres containing bevacizumab |
-
2013
- 2013-08-06 CN CN201310337426.1A patent/CN103405766B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102548548A (en) * | 2009-06-10 | 2012-07-04 | 米拓科技有限责任公司 | Pharmaceutical composition for use in medical and veterinary ophthalmology |
| CN102988301A (en) * | 2012-12-26 | 2013-03-27 | 温州医学院 | Preparation method of long-acting sustained-release microspheres containing bevacizumab |
Non-Patent Citations (1)
| Title |
|---|
| 常岩等: "贝伐单抗眼液对兔眼角膜新生血管抑制作用的实验研究", 《眼科新进展》, vol. 30, no. 7, 31 July 2010 (2010-07-31), pages 605 - 611 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103405766B (en) | 2016-01-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10688092B2 (en) | Compositions and methods of using nintedanib for improving glaucoma surgery success | |
| MX2012005816A (en) | Use of prostaglandins f2alpha and analogues for the healing of corneal and conjunctival lesions. | |
| AU2017301410B2 (en) | Multikinase inhibitors and uses in ocular fibrosis | |
| JP2009515921A (en) | Pharmaceutical composition free of dexpantenol, calcium ions and phosphate, and the use of calcium chelators and ophthalmically compatible viscosity modifiers | |
| CN107569494A (en) | Treatment of macular edema eye drops with Difluprednate | |
| CN102085203B (en) | Ophthalmic preparation of levofloxacin and prednisolone acetate and preparation method thereof | |
| CN102579334A (en) | Nasal drops containing sodium hyaluronate and preparation method thereof | |
| KR101723703B1 (en) | Ketorolac tromethamine compositions for treating or preventing ocular pain | |
| CN104606666B (en) | BFGF bovine basic fibroblast growth factor eye drop | |
| CN102920722A (en) | Ophthalmic preparation for treating fundus diseases | |
| CN103977011A (en) | Travoprost and timolol-containing ophthalmic gel and preparation method thereof | |
| CN103405766B (en) | A kind of bevacizumab eye drop and preparation method thereof | |
| CN110859835B (en) | Application of butylphthalide in preparation of medicine for treating corneal injury | |
| CN110812323B (en) | Ophthalmic composition, preparation method and application thereof | |
| RU2475248C1 (en) | Ophthalmic cross-linking agent-2 | |
| CN112022799A (en) | High-permeability local anesthetic gel and preparation method thereof | |
| CN112891326A (en) | Natamycin-loaded alginic acid gel medicine film and preparation method thereof | |
| RU2646452C1 (en) | Ophthalmological means for ultraviolet corneal crosslinking | |
| RU2644701C1 (en) | Method of conservative treatment of adapted penetrating wounds of the cornea | |
| CN112220749B (en) | Mizoribine and application of composition containing mizoribine | |
| CN111437252B (en) | Ophthalmic preparation containing erigeron breviscapus extract, preparation method and application | |
| CN102018656A (en) | Eye gel containing latanoprost used as effective component and preparation method thereof | |
| CN103040837A (en) | Ophthalmologic intraocular pressure reduction drug for external use | |
| CN116509993A (en) | Medicine for preventing and treating retinopathy and preparation method thereof | |
| RU2340327C1 (en) | Ophthalmologic gel and method of its preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |